The field of engineering has made substantial advances in nanotechnology, particularly in materials science and the molecular construction of nanoscale devices. In this proposal, the PI (Rzigalinski) and co-PI (Seal) have merged the studies of cell biology and nanoscale materials science to intervene in a common biomedical pathology, that being free radical cell damage and aging. We have engineered cerium oxide nanoparticles, 2-20 nm, by a novel non-agglomeration modified sol-gel process and assessed the activity of these particles in a tissue culture model using rat brain cells. Our preliminary data suggests that cerium oxide nanoparticles prolong brain cell longevity in culture, by 2-3 fold. Aged neurons in nanoparticle treated cultures maintained functional synaptic connections and had normal intracellular calcium signaling. Further, cerium oxide nanoparticles reduced hydrogen peroxide (H2O2) and UV light - induced cell injury by over 65%. We hypothesize that the unique structure of cerium oxide nanoparticles, with respect to valence structure and oxygen defects, promotes cell longevity and decreases toxic insults by scavenging free radicals. In this proposal we will synthesize and further characterize the physical and chemical properties of cerium oxide nanoparticles, and determine their behavior in physiologically relevant fluids and in the intracellular environment. We will further dissect the role of nanoparticles in cell longevity and determine their mechanism of action. Using microarray technology, alterations in gene transcription in control and nanoparticle treated cells will be during their lifespan. Lastly we will examine the ability of cerium oxide nanoparticles to increase longevity in the fruit fly. These studies will provide substantial insight into the pathology of aging and age-associated disorders and initiate a nanotechnological approach to pharmacotherapy.